Benzinger, Tammie L.S.

Abstract Background Amyloid‐Related Imaging Abnormalities (ARIA), an adverse event associated with Alzheimer's disease anti‐amyloid immunotherapies, occur in the form of edema or sulcal effusion (ARIA‐E) and microhemorrhages and superficial siderosis (ARIA‐H). Conventional teaching is that ARIA‐H is permanent hemosiderin staining of the brain. In clinical trials we have noticed that some ARIA‐H microhemorrhages that occur with regional ARIA‐E appear to later resolve. The goal of this study is to illustrate that, opposed to current understanding, some ARIA‐H microhemorrhages may resolve. Methods We identified participants from the Dominantly Inherited Alzheimer's Network Trial Unit (DIAN‐TU) and open label extension (OLE) gantenerumab studies that had ARIA‐E and at least one ARIA‐H microhemorrhage. The T2* GRE sequence from all available MRI exams in a patient were co‐registered and reviewed by a board‐certified neuroradiologist. Individual microhemorrhages were tracked over the serial exams. We defined disappearing/resolving microhemorrhages as those appeared with or following ARIA‐E, were visualized on at least 2 MRI exams, and were subsequently not visualized on at least 2 MRI exams. Results A total of 12 patients met inclusion criteria of which 5 (41%) had microhemorrhages that resolved over 10‐40 months follow‐up after the incident ARIA. These microhemorrhages occurred in clusters in the region of ARIA‐E, and only some of the regional microhemorrhages resolved over follow‐up. Examples are shown in Figures 1‐3. Conclusions The disappearance (resolution) of ARIA‐H microhemorrhages is relevant to the management and continued dosing of patients receiving anti‐amyloid immunotherapies as this is guided by the presence of ARIA (including cumulative treatment emergent microhemorrhages) as well as clinical symptoms. A microhemorrhage number alone may not be indicative of the potentially dynamic nature of ARIA‐H.

Abstract Background Alzheimer Disease (AD) pathology evolves over decades, and understanding this progression is critical to the understanding of the disease and timing therapeutic interventions. Since individuals with Autosomal Dominant AD (ADAD) develop symptoms around the same age as their parent, it is possible to predict symptom onset and stage individuals by their estimated years to symptom onset (EYO). This approach does not generalize to other forms of AD, thus there is a pressing need for the timecourse of ADAD to be defined in broadly relevant terms. The objective of this project is to validate the Sampled Iterative Local Approximation (SILA) algorithm in a cohort with a known disease timecourse. SILA generates an estimate of time from amyloid positivity (A time ) based on longitudinal PET data. Method We evaluated A time in a longitudinal ADAD sample ( N = 316) with PET PiB data in three ways. First, we compared predicted age at amyloid positive (A+) to observed age at A+ for individuals who became A+ during enrollment. Next, using linear regression, we compared estimated age at A+ to estimated age at symptom onset (EYO=0). Finally, we used generalized additive models to compare the amount of variance in concurrent cognitive performance explained both A time and EYO. Result We observed a mean average error of 1.15 years between actual age at A+ ( N = 26) and the SILA‐predicted A time . Across all participants, SILA‐estimated age at A+ explained 39% of the variance in estimated age at symptom onset ( β = 0.918, p < 0.0001). Finally, we observed a nonlinear association between cognition and both A time and EYO. A time explained 19% of the variance in the general cognitive composite while EYO explained 43% of the variance. Conclusion SILA produces a valid estimate of time‐from‐amyloid positivity in ADAD. This work allows for disease stage in ADAD to be compared to staging for broad forms of AD, which was not previously possible using EYO. However, this work also illustrates that there is a high degree of heterogeneity in preclinical disease duration that is not explained by amyloid alone.